Halogenated hydroxystilbazoles and derivatives thereof



Patented July 3, 1951 UNITED STATES PATENT OFFICE HALOGENATED HYDROXYSTILBAZOLES AND DERIVATIVES THEREOF Dcmenick Papa, Brooklyn, N. Y., and Erwin Schwenk and Erwin Klingsberg, Montclair, N. J assigncrs to Schering Corporation, Bloomfield, N. 3., a corporation of New Jersey No Drawing. Application October 15, 1946, Serial No. 703,282

13 Claims.

This invention relates to a new group of amebicidal compounds characterized by containing a halogenated h-ydroxyphenyl group attached to a nitrogen heterocyclic ring through a two-carbonatom chain;

The compounds of the invention are derivatives of wherein R is a member of the group consisting of pyrindine, quinoline and their lower alkyl mono-substitution products, X is an aliphatic hydrocarbon chain of two carbon atoms one carbon atom of which is attached to a carbon atom. of the heterocyclic ring and the other carbon atom of which is attached to a carbon atom. of" the phenyl ring, and Hal represents a halogen. of the group consisting of chlorine, bromine and iodine.

The compounds of the invention are active amebicidal agents with little or no toxic efiect. In general, they are also bactericidal agents and are therefore particularly useful in the treatment of. amebic disorders as they are likewise effective against the bacterial infections which are typically concomitants of amebic infections.

The compounds of the invention may be prepared by condensing a methyl pyridine with. an

aromatic aldehyde. The resulting stilbazole' may then be subjected to hydrogenation and halogenaticnby known methods. For example, by condensing a-picoline (I) with p-hydroxybenzaldehyde (II) in the presence of acetic anhydride, there is obtained 4-hydroXy-a-stilba-zole (III) which on reduction and iodination gives 3,5-diiodol-hydroxy-adihydrostilbazole (IV) (a (3,5 diiodo 4 hydroxy p phenethyD- l pyridine). The reactions may be represented by the following equations:

CHO

CH=CHOH m 1 om-omQon Bromination of 4'-hydroxy-a-dihydrostilbazole (V) gives 3",5.-dibrom' -4- hydroxy dihydrostilbazole (VI) (:1 -(3,5- dibromo-lhydroxy-fiphenethyDpyridine).

In place of w-picoli'ne or p-hydroxybenzaldehyde, there may besubstituted" other pyridine derivatives or other aromatic aldehydes, and thus 50 various isomeric or analogous compounds may 3 be obtained. She following equations illustrate the preparation of several different types of halogenated stilbazoles and dihydrostilbazoles.

1. Condensation of lutidine (VII) with 3,5- diiodol-hydroxybenzaldehyde (VIII) to 2-(3,5-

2. Condensation of v-picoline (X) with ohydroxybenzaldehyde (XI) to 'y-(3,5-diiOdo-2 hydroxystyryl) pyridine (XII) CH3 OH=CH N OH N cno X XI XII 3. Condensation of nitrobenzaldehyde (XIII) and -picoline (X), reduction of the nitro group and double bonds, and iodination and diazotization for the removal of the amino group gives (3,5-dii0d0-fi-phenethy1) pyridine (XIV) CH3 N02 (4 steps) X XIII XIV 4. Condensation of a-picoline (I) with p-hydroxybenzaldehyde (II) and reduction of the double bond and pyridine ring system followed b iodination of the hydrogenated product gives 0. (3,5-diiodo-4-hydroxy p phenethyDpiperidine (XV).

CH3 H N N l H I II 7 4 results a-(3,5-diiodo-4=-hydroxy B phenethyl) quinoline.

CH3 N I XVII Another illustration of the application to the quinoline ring system is the use of nitrobenzaldehyde (XIII) and methylquinoline. After several chemical manipulations, as previously illustrated, there results a-(3,5-diiodo-p-phenethyl)- quinoline, of the following formula:

I O3omom-Q Most of the substances described have groups which can be further substituted. For example, the hydroxy group may be converted into derivatives, such as the acetoxy, the methoxy, the carbomethox etc., in the known manner. 3',5'- diiodo-4-hydroxy-e-dihydrostilbazole, on treatment with chloracetic acid in the known manner, gives the a-(3,5-diiodo-4-carbomethoXy-[3-phenethyl) pyridine of the following formula:

1 N CHrCHr O c1120 0 OH By condensation of two molecules of a benzaldehyde with a dimethyl pyridine bis-styryl pyridines and bis-phenethyl pyridines may be obtained. For example, condensation of 2 mols of 4-hydroxybenzaldehyde (II) with lutidine (VII) followed by hydrogenation and iodination gives the c d-bis(3,5-diiodoi-hydroxyphenethyl) pyridine of the following formula:

An interesting feature of the substances of the invention is the basic function which renders them soluble in acid media. Such compounds on oral administration dissolve in the stomach and thus constitute contrast agents for this organ. It is possible to isolate the hydrochlorides of many of these iodinated condensation products, and in this form they are reasonably soluble in water. Their use as contrast agents isnot necessarily limited by the presence of the basic group, since they also contain alkali-soluble group's. Thus, these substances are useful in the visualization not only of the stomach but also'of other organs. 7

The various compounds which have been described above may be subjected to further hydrogenation than the elimination of the aliphatic double bond. For example, in the catalytic high pressure hydrogenation of 4'-hydroxy-m-stilbazole, there may be isolated in addition to the dihydrn derivative the following two substances:

The substance with the reduced pyridine ring may be methylated and iodinated to give a-(3,5'- diiodo-4=-hydrcxy-;8-phenethyl) -N-methylpiperidine of the following formula:

HQH

This procedure may also be applied to the other compounds described in the examples.

Many variations, in the methods of synthesis described may be made without departing from the principles of the invention.

The following examples are illustrative of the various methods of obtaining the compounds of the invention. Temperatures are in degrees centigrade.

Example 1 .3,5"-diiodo-2-hyd1'oxy-y-dihydr0- stilbazole 19.7 g. of 2'-hydroxyy-stilbazole is hydrogenated in accordance with known methods. The hydrogenated product, after isolation and recrystallization from aqueousethanol, forms long, fine, white needles melting at 164 -16,5.

19.9 g. of the recrystallized, hydrogenated hydroxystilbazole is dissolved in I200 cc. of water in which 80- g. of sodium hydroxide have been dissolved. To this solution there is added dropwise, with stirring, a solution of 50.8 g. of KI and 50.8 g. of iodine dissolved in 500 cc. of water. It is recommended that the iodination be carried out with the exclusion of light, since the, iodo compound is somewhat sensitive to light. When I the iodination is completed, the reaction mixture is treated with sulfur dioxide and then acidifled to litmus paper with acetic acid. The crystalline product after filtration is recrystallized either from aqueous alcohol or from a mixture of chloroform and petroleum ether and then melts at 146-147".

2.3',5'-0liiool0-2-hydroxy-a-dihydrostilb azole This compound is prepared from Z-hYfllOXY-astilbazole as described in Example 1 and melts at 126-128", after recrystallization from dilute ethanol.

Example 3.-3',5-diiodo-4'-hydroxy-a-dihydrostz'lbazole This compound is prepared from 4J-hydroxya-stilbazole as described for Example 1, and after recrystallization from aqueous alcohol melts at 170-171".

Example Example 4.-3',5'-diiodo4'-hydroxy-' -dihydrostilbazole This compound is prepared from 4'-hydroxy- 'y-stilbazole as described under Example 1, and. after recrystallization from aqueous alcohol melts atv 163164.

Example 5.-3',5'-diiodo-4 -acetoxy-6-methyl-astilbazole 20' g. 3,5-diiodo-4-hydroxybenzaldehycle and 20 cc. of 2,6-lutidine are refluxed for 20-30 hours in 100 cc. of acetic anhydride. The reaction is cooled, poured into methanol, filtered, and then recrystallized from 95% ethanol. The acetoxy compound separates in long, fine, white needles melting at 188-189".

Example 6.3,5'-diiodo-4'-hydToxy-6-methyla.--stilbazole This compound results from that prepared under Example 5 by hydrolysis with alcoholic alkali. After crystallization from aqueous alcohol, it melts at 20-1202.

Example 7 .-w,'-Bis- (3,5-dz'i'odo-4hydroxyphenethyl) pyridine Example 8.a-(3,5-diiodo-4-acetoxystyryl)quinol'lne.

This iodo derivative is prepared from quinaldine and 3,5-diiodo-4-hydroxybenzaldehyde by refluxing in acetic anhydride. The, compound is isolated in the usual manner, and after crystallization from ethanol melts at 187-189.

Example 9.a(3,5-diiodo-4'-hydroxystyryl) quz'nolz'ne This compound is prepared from the acetoxy derivative described under Example 8 by hydrolysis with sulfuric acid in ethyl alcohol. The hydroxy compound is isolated. in the knownv manner, and after recrystallization from alcohol melts at approximately 250 with decomposition.

Example 10.3",5dibrom-2-hy0lroxy-a-dihydrostillmzole 10 g. of 2'-hydroxy-dihydro-a-stilbazole is brominated with 16.3 g. of bromine in 30 cc. of acetic acid at room temperature with stirring. The addition of bromine is made over a period of about one hour and at the end of the addition a red compound separates out. After adding 500 cc. of water, the mixture is buffered with sodium acetate. A white crystalline material separates which is recrystallized from dilute ethanol. The dibrom compound separates in fine white needles melting at 116.5117.5.

Example 11.3',5'-dichlo1i0-2'-hydroxy-a-idihydrostilbazole 5 g. of 2-hydroxy-a-dihydrostilbazole is dissolved in acetic acid and with stirring 3.84 g. of

chlorine in acetic acid is added dropwise to this 100 for approximately 6 hours.

solution. After the addition, the solution is stirred for 20 minutes. The reaction mixture 'is then buffered with sodium acetate giving 4.8 g. of light brown solid melting at 114-116". Recrystallization from dilute ethanol gives pure white platelets melting at 116.5-117".

Example 12.-Reduction products of 4- hyd1oa:y- 1 I r a-s'tilbazole A solution of 19.7 g. of 4'-hydroxy-a-stilbazole in 300 cc. of ethanol is hydrogenated over Raneys nickel catalyst at an initial pressure of approximately 1500 pounds. The temperature of the hydrogenation was maintained between 80 and After filtration of the catalyst, the ethanol solution is evaporated and diluted with water. The resulting white solid is leached with hot dilute sodium hydroxide and wherein R is a member of the group consisting of pyridine, quinoline and their lower alkyl monosubstitution products, X is an aliphatic hydrocarbon chain of two carbon atoms onecarbon atom of which is attached to a carbon atom of the heterocyclic ring and the other carbon atom of which is attached to a carbon atom of the phenyl ring, and Hal represents a halogen of the group consisting of chlorine, bromine and iodine.

2. Compounds of the general formula wherein X is an aliphatic hydrocarbon chain of two carbon atoms one carbon atom of which is attached to a carbon atom of the pyridine ring and the other carbon atom of which is attached to a carbon atom of the phenyl ring, and Hal represents a halogen of the group consisting of chlorine, bromine and iodine.

3. Compounds of the general formula OH Z i 8 wherein X is an aliphatic hydrocarbon chain of two carbon atoms one carbon atom of which is attached to a carbon atom of the pyridine ring and the other carbon atom of which is attached to a carbon atom of the phenyl ring, Z represents a lower alkyl group, and Hal represents a halogen of the group consisting of chlorine, bromine and iodine. I

4. Compounds of the general formula wherein X is an aliphatic hydrocarbon chain of two carbon atoms one carbon atom of which is attached to a carbon atom of the pyridine ring and the other carbon atom of which is attached to a carbon atom of the phenyl ring, and Hal represents a halogen of the group consisting of chlorine, bromine and iodine.

5. Compounds as defined in claim 2 wherein a carbon atom of X is attached to the 2-position of the pyridine ring.

6. Compounds as defined in claim 2 wherein Hal is iodine. H

7. Compounds as defined in claim 2 wherein X is CH:CII-.

8. Compounds as defined in claim 2 wherein X is CH2.CH2-.

9. a-(3,5-diiodo-4-hydroxy-e-phenethyl) Pyridine.

REFERENCES CITED The following references are of record in the .file of this patent:

UNITED STATES PATENTS OTHER REFERENCES Young: J. Org. Chem, vol. 10, pages 67 and 68 (1945). 

1. COMPOUNDS OF THE GENERAL FORMULA 